Mélanie Eyries, David Montani, Barbara Girerd,Nicolas Favrolt, Marianne Riou, Laurence Faivre, Grégoire Manaud, Frédéric Perros, Stefan Gräf, Nicholas W. Morrell, Marc Humbert, Florent Soubrier
European Respiratory Journal 2020; DOI: 10.1183/13993003.02165-2019
Abstract
Background Beyond the major gene BMPR2, several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study.
Methods We prospectively analysed the KDR gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.
Results Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for hemoglobin (DLCOc) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low DLCOc, or have only decreased DLCOc, whereas non-carriers relatives have normal DLCOc. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal DLCOc.
Conclusion We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low DLCOc and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.
Footnotes
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Conflict of interest: Dr. EYRIES has nothing to disclose.
Conflict of interest: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, outside the submitted work.
Conflict of interest: Dr. GIRERD has nothing to disclose.
Conflict of interest: Dr. FAVROLT has nothing to disclose.
Conflict of interest: Dr. Riou has nothing to disclose.
Conflict of interest: Dr. FAIVRE has nothing to disclose.
Conflict of interest: Dr. Manaud has nothing to disclose.
Conflict of interest: Dr. Perros has nothing to disclose.
Conflict of interest: Dr. Gräf has nothing to disclose.
Conflict of interest: Dr. Morrell reports personal fees from Morphogen-IX, outside the submitted work.
Conflict of interest: Dr. Humbert reports personal fees from Acceleron, personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, personal fees from United Therapeutics, outside the submitted work.
Conflict of interest: Dr. SOUBRIER has nothing to disclose.
- Received November 7, 2019.
- Accepted January 2, 2020.
- Copyright ©ERS 2020
